Gemcitabine and CHK1 Inhibition Potentiate EGFR-Directed Radioimmunotherapy against Pancreatic Ductal Adenocarcinoma

Al-Ejeh, Fares; Shi, Wei; Kalimutho, Murugan; Miranda, Mariska; Nagrial, Adnan; Chou, Angela; Biankin, Andrew V.; Grimmond, Sean M.; Brown, Michael P.; Khanna, Kum Kum

doi:10.1158/1078-0432.ccr-14-0048

Cited by 35 publications

(27 citation statements)

References 46 publications

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“…It will be pivotal to monitor the effect of PARP inhibition in combination with PRRT closely in an in vivo model to optimize the timing of the combination regimen in order to reach maximum effect on the tumor and minimal normal tissue damage. Interestingly, triple combination treatment experiments in triple-negative breast cancer and pancreatic ductal adenocarcinoma xenograft models using radioimmunotherapy, chemotherapy and DDR inhibitors showed promising results in tumor eradication 21, 22.…”

Section: Discussionmentioning

confidence: 99%

Potentiation of Peptide Receptor Radionuclide Therapy by the PARP Inhibitor Olaparib

et al. 2016

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Metastases expressing tumor-specific receptors can be targeted and treated by binding of radiolabeled peptides (peptide receptor radionuclide therapy or PRRT). For example, patients with metastasized somatostatin receptor-positive neuroendocrine tumors (NETs) can be treated with radiolabeled somatostatin analogues, resulting in strongly increased progression-free survival and quality of life. There is nevertheless still room for improvement, as very few patients can be cured at this stage of disease. We aimed to specifically sensitize replicating tumor cells without further damage to healthy tissues. Thereto we investigated the DNA damaging effects of PRRT with the purpose to enhance these effects through modulation of the DNA damage response. Although PRRT induces DNA double strand breaks (DSBs), a larger fraction of the induced lesions are single strand breaks (expected to be similar to those induced by external beam radiotherapy) that require poly-[ADP-ribose]-polymerase 1 (PARP-1) activity for repair. If these breaks cannot be repaired, they will cause replication fork arrest and DSB formation during replication. Therefore, we used the PARP-1 inhibitor Olaparib to increase the number of cytotoxic DSBs. Here we show that this new combination strategy synergistically sensitized somatostatin receptor expressing cells to PRRT. We observed increased cell death and reduced cellular proliferation compared to the PRRT alone. The enhanced cell death was caused by increased numbers of DSBs that are repaired with remarkably slow kinetics, leading to genome instability. Furthermore, we validated the increased DSB induction after PARP inhibitor addition in the clinically relevant model of living human NET slices. We expect that this combined regimen can thus augment current PRRT outcomes.

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Section: Discussionmentioning

confidence: 99%

Potentiation of Peptide Receptor Radionuclide Therapy by the PARP Inhibitor Olaparib

et al. 2016

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“…Preclinical studies utilizing the CHK1 inhibitors MK8776 and LY2603618, with gemcitabine-based chemoradiation, showed synergistic effects to induce apoptosis of PDAC cells (91,92). The combination of gemcitabine, a CHK1 inhibitor, PF-477736, and Lutetium-177-labeled anti-EGFR antibody leads to extensive DNA damage, apoptosis, and tumor degeneration in patient-derived xenografts (93). Additional preclinical studies with a tumor stem cell marker Doublecortin-like kinase 1 (Dclk1) inhibitor, LRRK2-IN-1 (LRRK), showed decreased expression of phosphorylated Chk1 (94).…”

Section: Atm Inhibitorsmentioning

confidence: 99%

ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications

Armstrong

Schultz

Azimi-Sadjadi

et al. 2019

Molecular Cancer Therapeutics

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Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies with very few therapeutic options to treat advanced or metastatic disease. The utilization of genomic sequencing has identified therapeutically relevant alterations in approximately 25% of PDAC patients, most notably in the DNA damage response and repair (DDR) genes, rendering cancer cells more sensitive to DNA-damaging agents and to DNA damage response inhibitors, such as PARP inhibitors. ATM is one of the most commonly mutated DDR genes, with somatic mutations identified in 2% to 18% of PDACs and germline mutations identified in 1% to 34% of PDACs. ATM plays a complex role as a cell-cycle checkpoint kinase, regulator of a wide array of downstream proteins, and responder to DNA damage for genome stability. The disruption of ATM signaling leads to downstream reliance on ATR and CHK1, among other DNA-repair mechanisms, which may enable exploiting the inhibition of downstream proteins as therapeutic targets in ATM-mutated PDACs. In this review, we detail the function of ATM, review the current data on ATM deficiency in PDAC, examine the therapeutic implications of ATM alterations, and explore the current clinical trials surrounding the ATM pathway.

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“…Al-Ejeh et al proposed an effective pancreatic ductal adenocarcinoma (PDAC) treatment using a combination of chemotherapy (gemcitabine), Checkpoint kinase 1 (CHK1) inhibitor PF-477736, and epidermal growth factor receptor (EGFR)-targeted radioimmunotherapy ( 177 Lu-labeled anti-EGFR antibody) in cellline models and patient-derived xenografts. This combined triple therapy was well tolerated in mice and effective in PDAC tumors, representing a potential therapy option (33). …”

Section: Radiolabeled Antibodiesmentioning

confidence: 99%

Targeted radionuclide therapies for pancreatic cancer

et al. 2015

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Pancreatic malignancies, the 4th leading cause of cancer deaths, have an aggressive behavior with poor prognosis, resulting in a five-year survival rate of only 4%. It is typically a silent malignancy until patients develop metastatic disease. Targeted radionuclide therapies of cancer such as radiolabeled peptides which bind to the receptors overexpressed by cancer cells and radiolabeled antibodies to tumor-specific antigens provide a viable alternative to chemotherapy and external beam radiation of metastatic cancers. Multiple clinical trials of targeted radionuclide therapy of pancreatic cancer have been performed in the last decade and demonstrated safety and potential efficacy of radionuclide therapy for treatment of this formidable disease. While a lot progress has been made in treatment of pancreatic neuroendocrine tumors with radiolabeled with 90Y and 177Lu somatostatin peptide analogues, pancreatic adenocarcinomas remain a major challenge. Novel approaches such as peptides and antibodies radiolabeled with alpha emitters, pre-targeting, bispecific antibodies and biological therapy based on the radioactive tumorlytic bacteria might offer a potential breakthrough in treatment of pancreatic adenocarcinomas.

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Gemcitabine and CHK1 Inhibition Potentiate EGFR-Directed Radioimmunotherapy against Pancreatic Ductal Adenocarcinoma

Cited by 35 publications

References 46 publications

Potentiation of Peptide Receptor Radionuclide Therapy by the PARP Inhibitor Olaparib

Potentiation of Peptide Receptor Radionuclide Therapy by the PARP Inhibitor Olaparib

ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications

Targeted radionuclide therapies for pancreatic cancer

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